Project Summary Pain can be a serious medical problem. While it is firmly established that hyperexcitability of dorsal root ganglion (DRG) sensory neurons often contributes to neuropathic and inflammatory pain, the cellular and molecular changes that underlie this hyperexcitability are not fully understood. This lack of knowledge has hindered the development of better therapeutics. Studies indicate that sodium channel properties are altered by inflammation and nerve injury. We have compelling evidence that increased resurgent current activity is involved in abnormal electrical excitability in sensory neurons, and in inherited and acquired pain syndromes. Although these currents are crucial determinants of spontaneous and high-frequency firing in neurons, our understanding of the molecular mechanisms that regulate them in sensory neurons is incomplete. We have developed in vivo and in vitro approaches for manipulating proteins involved in resurgent current generation that uniquely positions us to investigate the roles of these currents in sensory neuron function. In this project we propose to 1) Determine how Fibroblast Growth Factor Homologous Factors (FHFs) regulate Nav?4?s ability to generate resurgent currents in DRG neurons. 2) Determine crucial molecular determinants of resurgent current generation. 3) Identify the roles of TTX-R and TTX-S resurgent currents in selected pain conditions, including peripheral inflammation, oxaliplatin-induced neuropathy, sickle cell disease and inherited small fiber neuropathy. 4) Determine how cannabinoids target resurgent currents in sensory neurons. This research will provide fundamental insight into how resurgent sodium currents are regulated and how they can be manipulated, increasing our knowledge of cellular and molecular mechanisms of pain and facilitating the discovery of new therapeutics for pain and other disorders of cellular excitability.